Stereoselective process for the preparation of 2-amino-ethanol derivatives having a central analgesic activity and intermidiates thereof

Abstract

A stereoselective process for the preparation of the compounds of formula ##STR1## wherein R, R 1 , R 2 , a and b have the meanings reported in the specification, is described. The compounds of formula I have a remarkable central analgesic activity and they are useful in the pharmaceutical field.

What we claim is: 
     
       1. A stereoselective process for the preparation of any stereoisomer of the compounds of formula ##STR4## wherein R is a phenyl optionally substituted by from 1 to 3 substituents selected from the class consisting of C 1  -C 4  alkyl, C 1  -C 4  alkoxy, hydroxy, halogen, and CF 3  ; R 1  and R 2 , which may be the same or different, are a linear or branched C 1  -C 6  alkyl, a C 3  -C 6  cycloalkyl; or   R 1  and R 2 , together with the nitrogen atom to which they are bonded, make a 5- or 6-membered heterocycle, which can further contain 1 or 2 heteroatoms selected from the class consisting of oxygen, nitrogen and sulfur, optionally substituted by 1 or 2 C 1  -C 4  alkyl groups; and   a and b mark the asymmetric carbon atoms; which process comprises: the transformation of the compound of formula (II) ##STR5##  in which a and b have the above reported meanings into the compound of formula (III) ##STR6##  in which R, a and b have the above reported meanings by reaction with a benzylamine of formula RCH 2  NH 2  (VII) in which R has the above reported meanings, with retention of configuration of the carbon atoms a and b;   the subsequent cyclization of the compound of formula (III) into the compound of formula ##STR7##  in which R, a and b have the above reported meanings; by conversion of the hydroxy group in a into the corresponding mesyl-derivative and subsequent ring closure in a dipolar aprotic solvent and in the presence of a base, with inversion of the configuration of the carbon atom a and retention of the configuration of the carbon atom b;   the hydrolysis of the compound of formula (IV) with an acid, in a solvent or mixture of solvents in order to obtain the compound of formula ##STR8##  in which X is a hydroxy or a chlorine or bromine atom and R 1 , a and b have the above reported meanings, with retention of configuration of the carbon atoms a and b;   the epoxidation of the compound of formula (V) in order to obtain the compound of formula ##STR9##  in which R 1 , a and b have the above reported meanings, with retention of configuration of the carbon atoms a and b;   the subsequent reaction of the thus-obtained compound of formula (VI) with a substituted amine of formula HNR 1  R 2  (VIII) in which R 1  and R 2  have the above reported meanings, in a solvent or mixture of solvents in order to obtain the compound of formula (I), with retention of configuration of the carbon atoms a and b.     
     
     
       2. A process according to claim 1 in which the mesyl-derivative of the compound of formula III is not isolated from the reaction environment but converted into the compound of formula IV. 
     
     
       3. A process according to claim 1 in which the substituted amine VIII is reacted with the epoxide of formula VI in 1:1 molar ratio or with a slight excess of the amine, in order to obtain the compound of formula I with retention of configuration of the carbon atoms a and b. 
     
     
       4. A process according to claim 1 in which the compound of formula V in which X=Br or Cl, is directly treated with the amine VIII in at least a molar amount that is double with respect to that of compound V, in order to obtain the compound of formula I with retention of configuration of the carbon atoms a and b. 
     
     
       5. A stereoisomer of a compound of formula ##STR10## in which R is a phenyl optionally substituted by from 1 to 3 substituents selected from the class consisting of C 1  -C 4  alkyl, C 1  -C 4  alkoxy, hydroxy, halogen, CF 3  ; a and b marking the asymmetric carbon atoms.   
     
     
       6. A stereoisomer of a compound of formula ##STR11## in which R is a phenyl optionally substituted by from 1 to 3 substituents selected from the class consisting of C 1  -C 4  alkyl, C 1  -C 4  alkoxy, hydroxy, halogen, CF 3  ; a and b marking the asymmetric carbon atoms.